Cycloalkenyl ethers of 17 beta-hydroxy androstanes



United States Patent 3,135,744 CYCLOALKENYL ETHERS 0F 17B-HYDROXYANDROSTANES Alberto Ercoli, Milan, and Rinaldo Gardi, Carate, Brianza,Italy, assignors to Francesco Vismara S.p-A., Casatenovo (Como), Italy,a corporation of Italy No Drawing. Filed Apr. 3, 1962, Ser. No. 184,680Claims priority, application Italy Apr. 12, 1961 13 Claims. (Cl.260239.55)

The invention relates to 17-(1-cycloalkenyl) ethers of 17fl-hydroxysteroids of the androstane series. More specifically, the new compoundsof this invention may be represented by the following structuralformula:

CH -CH A =,A ,A -dehydro analogs thereof, the 9oc-flll01'0-llfi-ol-derivatives of the A -dehydro analogs, the 11 8-01- derivativesof the A4-dehydro analogs and the ll-one derivatives of the A -dehydroanalogs,

and A ,A ,A -dehydro analogs thereof,

to CH HOW A ,A ,A ,A -dehydro analogs thereof, and lower alkyl ethersand lower alkanoyl esters of said compounds having the grouping (c) andthe dehydro analogs thereof,

A ,A ,A -dehydro analogs thereof, and l9-nor-A -dehydro analog thereof,

3,135,744 Patented June 2, 1964 no onj 0 \/I and The term lower alkyl asused herein includes saturated lower hydrocarbon radicals containingfrom 1 to 5 carbon atoms, inclusive, preferably methyl, ethyl, propyl,isopropyl, amyl and cyclopentyl. The term lower alkanoy means the acylresidue of an alkanoic acid containing from 1 to 3 carbon atoms,inclusive.

The new androstane derivatives of this invention, characterized byhaving at the 17,8-position an oxycycloalkenyl moiety of the structureabove indicated, possess valuable biological properties. They haveantitesticular, antisteatogenic, antiovulatory effects and particularlypronounced androgenic and/ or anabolic activity.

Preferred compounds of this invention are cyclopentenyl ethers of the17B-hydroxy androstane series more particularly the 17-cyclopentenylethers of: SOL-aHdIO- stane-17i3-ol-3-one, 5a-androstane-3a,17B-diol, A-androstene-17fi-ol-3-one, A -androstene-3B,17fi-diol, A-androstene-17fi-ol-3-one, A -androstadiene-17B-ol-3-one, 19 nor-A-androstene-17,8-01-3-one, 19-nor-A -androstene- 17fi-ol-3-one and9a-fiuoro-A -androstene-l15,1719-diol-3- one.

These compounds show a remarkable androgenic and/ or anabolic activity.For instance, the cyclopentenyl ethers of the first four 17,6-hydroxyandrostanes, above mentioned, have proved to be orally as potent asmethyl testosterone and the cyclopentenyl ether ofN-androstene-l7fi-ol-3-one exhibits by oral route three times theanabolic activity and two times the androgenic activity ofmethyltestosterone itself.

Moreover the cyclopentenyl ethers of 19-nor-A -androstene-l7 8-ol-3-oneand l9-nor-A -androstene-175-01-3- one show a ratio of anabolic toandrogenic activity 14 and 10 times respectively superior to that ofmethyltestosterone.

Generally the new cyclopentenyl ethers of the 17,8- hydroxy androstanesof this invention show an increased biological activity over thecorresponding free hydroxy parent steroids and are of greater value asandrogenic and/or anabolic agents as compared with other hydroxysteroids of biological significance, e.g. methyltestosterone, becausethe non-physiologically active methyl group is not present in thel7-position.

The new cycloalkenyl ethers of this invention are obtained by reactingat a temperature higher than 80 C.

the corresponding 17,8-hydroxy steroid of the androstane series with afunctional derivative of a five-or-six membered cyclic ketone theS-hydroxy group, if present, first being protected. The term functionalderivatives means the typical derivatives of the ketones with aliphaticalcohols, that is acetals, hemiacetals, enolethers, preferablydimethylor diethyl-acetals, methyl or ethyl enolethers or mixtures ofthese derivatives. Such functional derivatives can be prepared accordingto known methods, that is by heating cyclopentanone or cyclohexanonewith the appropriate alkyl orthoformate.

A suitable functional derivative is a mixture of diethyl acetal andethyl enol ether prepared by heating cyclopentanone or eyclohexanonewith ethyl orthoformate and ethyl alcohol in the presence of an acidcatalyst such as p-toluensulfonic acid. 3

The reaction between the functional derivative of cyclopentanone orcyclohexanone and the 17,8-hydroxy steroid, can be performed either inthe presence of suitable organic solvents or in their absence. Thesolvents which are most suitable to this purpose are those having aboiling point greater than 80 C., preferably benzene, toluene, dioxan,isoctane, and dimethylformamide. The reaction is carried out at atemperature in the range of from about 85 C. up to the boiling point ofthe solvent used and for from about 15 to 60 minutes. absence of thesolvents, the reaction is preferably carried out at from about 90-190 C.for about 30 minutes to 2 hours.

The reaction can also be performed in the presence of an acid catalyst,preferably a strong organic acid or a salt of a strong acid with anorganic base, for example 'p-toluensulfonic or benzenesulfonic acid orpyridine hydrochloride.

The desired 17-cycloalkeny1 ether is obtained, after eliminating thesolvent, if any, and removing the excess of cyclopentanone orcyclohexanonefunctional derivative reactant, by successivecrystallizations in the 'usual manner.

If the resulting steroid derivative contains a keto group 'in the3-position, it can be submitted, if desired, to a further step in orderto transform the 3-keto group into a hydroxy group by normal reductionmethods, for instance by treatment with lithium hydride or sodiumborohydride.

Alternatively, the 1'7-cycloalkenyl ethers of 3,175- dihydroxyandrostanes can be obtained by reacting a 3- lower alkanoyl ester of the3,17,8-dihydroxy steroid with the functional derivative ofcyclopentanone or cyclohexanone under the conditions above mentioned,the ester group at the 3-position can be hydrolyzed in an alkalinemedium and under such conditions, the ether group at the 17-position isstable, thus providing the l7-cycloalkenyl ether of the 3,17,8-hydroxysteroid.

The following examples are set forth as illustrating in detail thematerials and methods for the preparation of the new compounds but theyare not to be regarded as limiting the invention.

Example 1 150 cc. of cyclopentanone are heated to reflux for -1 hourwith 285 cc, of ethyl orthoformate, 306 cc. of absolute ethanol and1.425 g. of p-toluensulfonic acid.

After cooling, the mixture is treated with 1.05 g. of poresidue which istaken up with dilute methanol containing a few drops of pyridine. Thecrystalline product obtained In the Example 2 3 g. of2a-methyltestosterone in 5 cc. of dimethylformamide are treated with 30mg. of p-toluensulfonic acid and 5 cc. of cyclopentanone diethylacetal(obtained by treating cyclopentanone with orthoformic ether and dryethanol according to the method described in Rec. Trav.-Chim. 57, 136;1938).- I

The mixture is heated for 30 minutes at 180-190 C., then cooled andneutralized with a few drops of pyridine. After distillation underreduced pressure, there is obtained a residue which is taken up with amixture of methylene chloride-methanol. The product which separates oncooling consists of 1'7-cyclopentenyl ether of Zea-methyltestosterone,M, Pt. 154-155 C.; [a] (dioxan).

Example 3 Example 4 By treating a mixture of A -androstadiene-17,8-ol-3-one (2 g.), cyclopentanone diethyl-acetal (4 cc.) and ptoluensulfonicacid (30 mg.) in 250 cc. of isoctane as in the foregoing Example, the17-cyclopentenyl ether of A -androstadiene-17p-ol-3-one is obtained; M.Pt, 142- 144 C.; [a] =+23 (dioxan).

Example 5 3 g. of A -androstene-1'7p-ol-3-one in 5 cc. ofdimethylformamide solution are treated with 5 cc. of cyclopenta- 'nonediethyl-acetal and 30 mg. of benzensulfonic acid. The mixture is heatedat C. for about 1 hour, then cooled and neutralized with a few drops ofpyridine and the solvent distilled under vacuum. The residue is purifiedwith dilute methanol to give 17-cyclopentenyl ether of A-androstene-17fi-ol-3-one, M. Pt. 118-120 C.; [a] 60 (dioxan).

Example 6 i 3 g. of 19-nortestosterone are treated with 10 cc. of amixture of diethyl-acetal and ethyl enol ether of cyclopentanone as inExample 1 to give 17-cyclopentenyl ether of 19-nortestosterone, M. Pt.102-106 C.; [a] =+50 (dioxan).

Example 7 A mixture of 1.5g. of 5a-androstane-17fi-ol-3-one and 5 cc. ofdimethylformamide is treated with 3 cc. of cyclopentanone diethyl-acetaland 30 mg. of sulfosalicylic acid. The mixture heated for 30 minutes atISO- C., then distilled under reduced pressure after addition of a fewdrops of pyridine. The residue is purified with boiling dilute methanolto give 17-cyclopentenyl ether of Sa-androstane-17/i-ol-3-one, M. Pt.IOU-102 C.; [oz] =|-59 (dioxan).

Example 8 3 g, of 2-hydroxy methylene-Sa-androstane-17 8-01-3- one in 5cc. of dimethylformamide solution are reacted with 10 cc. ofcyclopentanone dimethyl-acetal and 30 mg. of p-toluensulfonic acid. Thereaction mixture is heated at 190 C. for about 1 hour, then neutralizedwith a few drops of pyridine and concentrated to dryness under reducedpressure. The residue, crystallized twice from methanol, yields17-cyclopentenyl ether of2-hydroxymethylene-5a-androstane-l7l3-ol-3-one; M. Pt. 168173 C.; [cc]=+58 (dioxan).

Example 9 5 g. of 5u-androstane-3a,17fi-diol-3-acetate (obtained byreduction of the corresponding 17-keto derivative with sodiumborohydride) in dimethylformarm'de solution are treated with 10 cc. ofcyclopentanone diethylacetal as in Example 2 to give the corresponding17-cyclopentenyl ether melting at 134136 C.; [a] =+32 (dioxan).

This product (1.5 g.), dissolved in 50 cc, of methanol, is treated underreflux for 2 hours with a solution of 0.5 g. of potassium carbonate in 5cc. of water. The reaction mixture gives upon concentration a residuewhich, purified with methanol, consists of 17-cyclopentenyl ether ofSa-androstane-B'a,17B-diol, M. Pt. 145147 C.; [:1 +30 (dioxan).

The same product is obtained by alkaline hydrolysis of 17-cyclopentenylether of a-androstane-3a,l7fl-diol- 3-propionate, M. Pt. 9192 C.; [a]:+35 (dioxan).

Example By treating 5a-androstane-3a,l7B-diol-3-n-butyl ether withcyclopentanone diethyl-acetal as in Example 2, the correspondingl7-cyclopentenyl ether is obtained, M. Pt. 121-122" C.; [a] :+l9.4(dioxan).

Similarly, 17-cyclopentenyl ether of 5a-androstane-3a,17B-diol-3-isopropyl ether is prepared, M Pt. 54-58 C.; [a] =+24(dioxan).

Example 11 2 g. of A -androstene-3B,17,8-diol 3-propionate (obtained bysodium borohydride reduction of the corresponding 17-keto derivative)are treated with 5 cc. of cyclopentanone diethylacetal, 8 cc. ofdimethylformarnide and 40 mg. of p-benzensulfonic acid. The mixture isheated for 30 minutes at 180190 C., then neutralized with a few drops ofpyridine and concentrated to dryness under reduced pressure. Theresidue, taken up with methanol, filtered and recrystallized frommethanol, yields 1 g. of l7-cyclopentenyl ether of A -androstene-3fi,l7fi-diol-3-propionate, M. Pt. 77-79 C.; [a] =34.5 (dioxan).

This product, dissolved in 30 cc. of methanol, is heated under refluxfor two hours with 0.6 g. of sodium carbonate in 5 cc. of watersolution. By concentrating the solution to dryness and purifying theresidue from methanol, there is obtained 17-cyclopentenyl ether of A-androstene-3B, 1713-diol, M. Pt. 115-11'7 C.; [a] =32 (dioxan).

The same product is obtained by alkaline hydrolysis of 17-cyclopentenylether of A -androstene-3fi,17,8-diol- 3-acetate.

Example 12 By operating according to the technique described in Example11, l7-cyclopentenyl ether of A -androstene- 3B,17;3-diol-3-isopropylether is obtained, M. Pt. 139- 140 C.; [u] :29.8 (dioxan).

Example 13 A -androstene-3a,17,8-diol-3-acetate is treated withcyclopentanone diethyl-acetal and ethyl enol ether as in Example 1 togive 17-cyclopentenyl ether of M-androstene- 30:,175-di0l 3-acetate. Theproduct, hydrolyzed with sodium carbonate in methanol solution as inExample 11,

yields the corresponding 17-cyclopentenyl ether of A-androstene-3a,17p-diol.

In the same manner, 17-cyclopentenyl ether of A-androstadiene-3a,17/3-dio1-3-acetate is obtained and converted onalkaline hydrolysis to l7-cyclopentenyl ether of A-androstadiene-3a,l7fi-diol.

Example 14 A mixture of 4 g. of A -androstene-3 11,17 B-diol-S-acetate,8 cc. of cyclopentanone diethyl-acetal, 400 cc. of toluene and 50 mg. ofpyridine hydrochloride is heated to reflux and distilled for about 15minutes. The remaining solution is then concentrated to dryness invacuo. The residue, purified from dilute methanol, yields the17-cyclopentenyl ether of A -androstene-3a,175-diol-3-acetate.Hydrolysis of the product with potassium carbonate in dilute methanolprovides the l7-cyclopentenyl ether of a -androstene- 3a,17 B-diol.

Example 15 2 g. of 17-cyclopentenyl ether of testosterone, obtained asdescribed in Example 1, are dissolved in cc. of ether and the solutionrefluxed for 1 hour with 3 g. of lithium aluminium hydride in 40 cc. ofanhydrous ether. After careful addition of water, the mixture isextracted with ether and the ethereal extracts collected and dried overanhydrous sodium sulfate. Evaporation of the solvent gives a solidresidue which crystallized from a mixture of methylene chloride-methanolconsists of the 17-cyclopentenyl ether of A -androstene-3fi,17fi-diol,M. Pt. 153155 C.; [a] =+54 (dioxan).

Analogously, 17-cyclopentenyl ether of A -androstadiene-l7fl-ol-3-one,prepared according to the Example 3, is converted by treatment withlithium aluminium hydride to 17-cyclopentenyl ether of A -androstadiene-3,13,17fi-diol.

Example 16 By treating cyclohexanone with ethyl orthoformate and dryethanol in the presence of p-toluensulfonic acid (according to themethod described in Rec. Trav. Chim. Pays Bas 57, 136; 1938)cyclohexanone diethyl acetal is obtained. 30 cc. of this product areadded to a mixture of 8 g. of A -androstene-17B-ol-3-one, 20 cc. ofdimethylformamide and 50 mg. of p-toluensulfonic acid. The reactionmixture worked as in Example 5 provides the 17-cyclohexenyl product;

A solution of 1 g. of sodium borohydride in 50 cc. of water is addeddropwise over 30 minutes to a stirred solution of 5 g. ofl7-cyclohexenyl ether of A -androstene- 17fi-ol-3-one in 200 cc. ofdimethylformamide maintained at a temperature of 20 C. The mixture isthen diluted with water and extracted with ether. The product obtainedby evaporation of the ethereal extract, is purified from methanol togive l7-cyclohexenyl ether of A -androstene-3B,l7,B-diol.

Example 17 A mixture of 2 g. of l9-nor-A -androstene--01- 3-one, 5 cc.of cyclopentanone diethyl-acetal, 30 mg. of p-toluensulfonic acid and 15cc. of dimethylformamide is heated for about 40 minutes at a temperatureof C. By operating as in Example 2, l7-cyclopentenyl ether of 19-nor-A-androstene-17fl-ol-3-one is obtained, M. Pt. 152154 C.; [oz] =+163(dioxan).

Example 18 A mixture of 3 g. of 5a-androstane-17 S-ol[3,2c]- isoxazole(prepared by reacting 2-hydroxy-methyleneandrostan-17fi-ol-3-one withhydroxylamine hydrochloride according to the method described byMarchetti and Donini, Gazz. Chim. It. 91, 1133; 1961), 5 cc. ofcyclopentanone diethyl-acetal, 400 cc. of isoctane and 40 mg. ofp-toluensulfonic acid is worked as in Example 3, to give17-cyclopentenyl ether of 5a-androstane-1713-ol- {3,2c1isoxazole, M. Pt.12-6l28 C.; [a] =+64 (dioxan).

7 Example 19 .By treating u-androstane-3a,17,3-diol-3-propionate withcyclohexanone diethyl-acetal as in Example 7, there is obtained17-cyclohexenyl ether of 5a-androstane-3u, 17fi-diol-3-propionate, M.Pt. 138139 C.; [cz] =+37 (dioxan) Hydrolysis with sodium carbonateprovides the corresponding17-cyclohexenyl ether of 5a-androstane-3a,17,8-diol. Analogously the 17-cyclohexenyl ether of 3,8-acetoxy- A-androstene-17fi-ol is obtained, M. Pt. 142-144 C.; [a] =26.4- (dioxan)which, by hydrolysis With aqueous potassium carbonate, as described inExample 11 yields the 17-cyclohexenyl ether of A -androstene-3,B,17,8-diol, M. Pt. 152-155" C.; [a] =19 (dioxan).

In the same manner are prepared:

1 g. of l-methyl-A -androstene-l7fi-ol-3-one (obtained as described inBer. 93, 1710; 1960), is treated with 3 cc. of cyclopentanonediethyl-acetal and 20 mg. of p-toluensulfonie acid in 200 cc. ofisoctane as in Example 3 to give 17-cyclopentenyl ether of l-methyl-A-androstene- 17 /3-ol3-0ne. 1

Similarly, 5a-androstane-17B-ol (prepared by Wolf- Kishner reaction ofthe semicarbazone of 17,8-hydroxyandrostane-3-one according to Ruyle, J.Organic Chem. 25, 1260; 1960), is reacted and converted to l7cyclopentenyl ether.

Example 21 1 g. of A -l9-nor-androstene-17 3-01 (obtained as describedin Chem. and Ind. 905, 1959), is treated with 4 cc. of cyclopentanonediethyl-acetal and 25 mg. of p-toluensulfonic acid in 200 cc. ofisoctane as illustrated in Example 3 to obtain the '17-cyclopenteny1ether of A -19-nor-androstene-175-01.

We claim:

1. A compound selected from the group consisting of a compound of theformula wherein n is one of the integers 1 and 2, a 2-hydroxymethylenederivative thereof, a A -dehydro analog thereof, a l-methyl derivativeof said A -dehydro analog, a M-dehydro analog thereof, aQa-fiUOI'O-llfi-Ol derivative of said A -dehydro analog, an 115-01derivative of said A -dehydro analog, an ll-one derivative of said A-dehydro analog, a Zen-methyl derivative of said A -dehydro analog, a A-dehydro analog thereof, and a A -dehydro analog thereof.

2. A compound selected from the group consisting of a compound of theformula GE -CH wherein n is one of the integers 1 and 2, a A -dehydroanalog thereof, a A -dehydro analog thereof and a A -dehydro analogthereof.

3. A compound selected from the group consisting of a compound of theformula 7 wherein n is one of the integers 1 and 2, a 3-lower alkylether thereof, a 3-lower alkanoyl ester thereof, a A -de hydro analogthereof, a 3-lower alkyl ether of said A -dehydro analog, a 3-loWeralkanoyl ester of said A dehydro analog, a A -dehydro analog thereof, a3-lower alkyl ether of said A -dehydro analog, a 3-lower alkanoyl esterof said A -dehydro analog, a A -dehydro analog thereof, a 3-lower alkylether of said A -dehydro analog, a 3-loWer alkanoyl ester of said Ai-dehydro analog, a A -dehydro analog thereof, a 3-lower alkyl ether ofsaid A -dehydro analog and a 3-lower alkanoyl ester of said A -dehydroanalog.

4. A compound selected from the group consisting of a compound of theformula 10. 17-cyc1openteny1 et er of A -andrstadiene-17/8- 01-3-one.

12. 17-cyc10penteny1 ether of 19-nor-A l -androstene- 17,3-01-3-0ne.

13. 17-eyc1openteny1 ether of 9a-fluor0-A -andr0stene-1l,8,i7;3-dic1-3-one.

ether of l9-ncr-A -androstene- References (liter! in the file of thispatent UNITED STATES PATENTS 2,846,452 Campbell Aug. 5, 1958 T53 FOREIGNPATENTS Great Britain Apr. 29, 1959 OTHER REFERENCES Butenandt et al.:Berichte, v01. 73, pages 206208,

Wflde et al: J.A.C.S., v01. 75, pages 53665369, 1953.

Rosenkranz et a 3.A.C.S., vol. 76, pages 50245026, 1954.

Huggins et aL: Endocrinology, vol. 57, pages 32, 1955.

Schering: Derwent Belgian Report No. 55A, page A25, Tune 30, 1959.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA
 4. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUNDOF THE FORMULA